Sulforaphane, A Dietary HDAC Inhibitor, and Prevention of DCIS Progression Project Summary Significant advances in diagnosis and medical management of ductal carcinoma in situ (DCIS) have markedly reduced disease progression and improved long-term survival. However, there are limited medically accepted options for neo-adjuvant therapy to improve surgical success;though it is common for women to seek alternative therapies in an attempt to improve outcome. Hence, there is a need for scientifically directed evaluation of dietary substances that may effectively inhibit the progression of DCIS. Inhibitors of histone deacetylases (HDAC) have generated considerable recent interest as novel chemoprotective agents because they target epigenetic events that can occur at various stages of cancer development. Pharmacological HDAC inhibitors have anti- cancer effects in breast cancer cells both in vitro and in vivo. However, the adverse effects of these agents make them undesirable for long-term use in women with pre- invasive disease (DCIS). Sulforaphane (SFN), a phytochemical found in cruciferous vegetables, has received recent attention as a potential chemopreventive agent, yet its precise mechanism of action remains unclear. Based on the studies with dietary HDAC inhibitors in prostate and colon cancer cells, and in healthy volunteers, we propose to examine these associations in a breast cancer model and test the effectiveness of supplemental SFN intake in improving biomarkers for prognosis and in altering HDAC activity in DCIS patients. This DIETARY approach to cancer prevention has several advantages over conventional pharmacological HDAC inhibitors, including less toxicity and ease of administration. The use of SFN as a chemopreventive approach is significant because of its relatively non-toxic nature and multiple biologically relevant anti-tumorigenic activities. PUBLIC HEALTH RELEVANCE: Significant advances in the diagnosis and medical management of ductal carcinoma in situ (DCIS) have markedly reduced disease progression and improved long-term survival. However, despite overall good outcomes, the effective treatment of DCIS still requires surgery and radiation therapy, and we need better methods of preventing disease progression. There are limited medically accepted options for neo-adjuvant therapy to improve surgical success, and the typical neo-adjuvant chemotherapy given for invasive disease does not impact DCIS outcome due, in part, to decreased penetration into the ductal space. Thus, it is common for women to seek alternative therapies in an attempt to improve outcome. Hence, there is a need for scientifically directed evaluation of dietary substances that may effectively inhibit the progression of DCIS. A number of epidemiologic studies have reported an inverse association between cruciferous vegetable intake and risk of breast cancer, though not all findings are consistent. Unfortunately, many of the population studies are limited by the imprecision of dietary assessment techniques, and the grouping of all diagnoses of breast cancer, regardless of stage, as a single outcome. It has been suggested that dietary compounds function as chemoprotection agents, by both blocking initiation and suppressing cell proliferation post- initiation and thus slowing disease progression. Sulforaphane (SFN), a phytochemical found in cruciferous vegetables has been demonstrated to inhibit breast cancer cell proliferation and enhance apoptosis, both in vitro and in vivo. More recently, the role of gene silencing via epigenetic alterations such as acetylation of histone structure has emerged an important factor in tumorigenesis and resistance to therapy in several cancers. Pharmacological inhibitors of histone deaceylases (HDAC) have induce apoptosis and decrease cancer cell proliferation in breast cancer cells both in vitro and in vivo. Based on the similarity of SFN and its metabolites to the conserved structure of HDAC inhibitors, we have gone on to demonstrate that dietary consumption of SFN limits tumor growth in animal models and decreases HDAC activity in human volunteers. We propose to conduct a randomized placebo-controlled trial to test the effectiveness of supplemental SFN intake in improving biomarkers for prognosis in DCIS patients and in altering HDAC activity. PUBLIC HEALTH RELEVANCE: The research proposed in this application is highly relevant because strategies that target epigenetic pathways have the potential to increase survival of DCIS patients, reduce health care costs associated with breast cancer, and improve the quality of life for thousands of American women. The successful completion of these smaller clinical studies will provide a strong scientific foundation for future large-scale human clinical intervention studies to combat breast cancer. These studies are also significant because of the potential to qualify or change recommendations for breast cancer patients and thereby increase their survival through simple dietary choices incorporating easily accessible and safe food products into a patient's diet.